Prostate cancer (PC) disproportionately affects African-Americans (AA). This study proposes to identify new genetic and obesity-related factors contributing to PC risk in persons of African descent, in a setting that offers special opportunities for such research. Results would be based on 960 histologically-confirmed nationwide incident cases and 960 population-based control men from Barbados, West Indies, -94% being African-Barbadians (AB). Study results have high applicability to AA. The AA and AB populations share the same ancestral origin and have similar PC patterns. These similarities suggest a role for inherited susceptibility in AA/AB, which could be due to ancestral genetic variants. Detection of these variants would be enhanced in AB because of lower admixture;results would be replicated in AA samples. We hypothesize a multigenic model of susceptibility involving insulin-related and steroid hormone pathways, which also may be mediated by environmental influences;central adiposity patterns would notably affect risk. AIM 1: To evaluate the contribution of body size to PC risk. This aim would be achieved by ascertaining relationships with anthropometric indices (which differ in AA/AB vs. others), weight history and other factors. AIM 2: To evaluate the relationship of PC to common genetic variants in hypothesized pathways, using a staged genotyping approach. Stage 1: we will genotype and analyze 800 SNPs (2kb SNP map) within select candidate genes involved in the insulin/IGF axis and steroid metabolism and regulation pathways among 900 AB PC cases and 900 AB controls. We will determine the haplotype block structure of these genes and subsequently determine risk estimates associated with PC for alleles at individual SNPs and haplotypes. Stage 2: we will validate the top 1% of all SNPs/haplotypes and all coding SNPs among the top 5% of SNPs in a set of 800 AA PC cases and 800 controls. The study has high public health relevance to AA. It would clarify reasons for PC risk in AA, by identifying new genetic and other risk factors. The study will use novel multigenic and multistage approaches, involving data on AA, and focus on relevant PC pathways. It will also determine the role of obesity-related factors, with results having potential for preventive interventions. Study data will allow comparisons of PC risk across the African diaspora, as well as being a resource to advance PC research in AA.